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IJRPC 2011, 1(3) Srinivasan et al. ISSN: 22312781
INTERNATIONAL JOURNAL OF RESEARCH IN PHARMACY AND CHEMISTRY
Available online at www.ijrpc.com
Review Article
ADVERSE DRUG REACTION-CAUSALITY ASSESSMENT
Srinivasan R* and Ramya G
PES College of Pharmacy, Department of Pharmacy Practice, 50 Ft. Road, Hanumanth Nager,
Bangalore, Karnataka, India.
*Corresponding Author: cdmseena@gmail.com
INTRODUCTION
Adverse drug reactions (ADRs) are considered
as one among the leading causes of morbidity
and mortality 1 . .The epidemiological
importance of ADR is justified by its high
prevalence rate – they cause from 3% to 6% of
hospital admissions at any age, and up to 24%
in the elderly population; they rank fifth
among all causes of death and, moreover, they
represent from 5 to 10% of hospital costs 2 . and
is a great cause of concern to the medical
profession. Every occasion when a patient is
exposed to a medical product, is a unique
situation and we can never be certain about
what might happen. A good example for this
is thalidomide tragedy in late 1950s and
1960s.Thalidomide prescribed as a safe
hypnotic to many thousands of pregnant
women caused severe form of limb
abnormality known as phocomelia in many of
the babies born to those women. It was a
seminal event that led to the development of
modern drug regulations aimed to identify,
confirm and quantify ADRs. An adverse drug
reaction (ADR) is any undesirable effect of a
drug beyond anticipated therapeutic effects
occurring during clinical use 14 . Hence every
health care professional who give advice to
patients need to know the frequency and
magnitude of the risks involved in medical
treatment along with its beneficial effects.
Recent epidemiological studies estimated that
ADRs are fourth to sixth leading cause of
death 3 . It has been estimated that
approximately 2.9-5% of all hospital admission
are caused by ADRs and as many as 35% of
hospitalised patients experience an ADR
during their hospital stay 4 . An incidence of
fatal ADRs is 0.23%-0.4%. 5 Although many of
the ADRs are relatively mild and disappear
when drug is stopped or dose is reduced,
others are more serious and last longer.
Therefore there is a little doubt that ADRs
increase not only morbidity and mortality but
also add to the overall health care cost 6, 7 .
Adverse drug reaction (ADR)
Definitions of ADRs exist, including those of
the World Health Organization (WHO) 8 .
Karch and Lasagna 9 and the Food and Drug
Administration (FDA) 10 .
WHO
Any response to a drug which is noxious and
unintended, and which occurs at doses
normally used in man for prophylaxis,
diagnosis, or therapy of disease, or for the
modification of physiological function.
Karch and Lasagna
Any response to a drug that is noxious and
unintended, and that occurs at doses used in
humans for prophylaxis, diagnosis, or therapy,
excluding failure to accomplish the intended
purpose.
FDA
For reporting purposes, FDA categorizes a
serious adverse event (events relating to drugs or
devices) as one in which “the patient outcome
is death, life-threatening (real risk of dying),
hospitalization (initial or prolonged), disability
(significant, persistent, or permanent),
congenital anomaly, or required intervention
to prevent permanent impairment or damage.
Classification of Adverse Drug Reactions
ADRs can be divided schematically into two
major categories:
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Type A and Type B (Table 1).
Type A reactions are common, predictable and
may occur in any individual. Type B ADRs are
uncommon and unpredictable and only occur
in susceptible individuals 11 .
Type A reactions are the most frequent and
can be observed in as many as 25–45% of
patients. These represent an exaggeration of
the known primary and/or secondary
pharmacological actions of the drug, they are
dose related and could probably be avoided
and/or foreseen 12 . Multi-factorial, involving
not only defects at multiple gene loci but also
environmental factors such as concomitant
infections. Most work has focused on enzyme
polymorphism in drug oxidation and
conjugation as risk factors for drug toxicity but
genes involved in cell repair mechanisms,
elaboration of cytokines and immune
responsiveness cannot be excluded to predict
individual susceptibility to different forms of
ADRs 12,14 . . Genetic polymorphisms are a
source of variation of drug response in the
human body. In relation to ADRs, most
interest has centred on the involvement of
pharmacokinetic factors and, in particular,
drug metabolism. However, there is now
increasing realization that genetic variation in
drug targets (Pharmacodynamic factors) might
also predispose to ADRs, although research
into this area is in its infancy 15 .
Mechanism by which ADR Occurs 16
ADRs can be classified as either
pharmacological reactions representing an
augmentation of the known pharmacological
actions of the drug or idiosyncratic reactions
that are not predictable. Pharmacological
reactions are most common, usually doserelated
and are due to the primary or
secondary pharmacological characteristics of
the drug. Factors that predispose to these
ADRs include dose, pharmaceutical variation
in drug formulation, pharmacokinetic or
pharmacodynamic abnormalities, and drugdrug
interactions. Pharmacological ADRs
occur when drug concentration in plasma or
tissue exceeds the “therapeutic window” or
when there is increased sensitivity to the drug
(even in concentrations considered normal for
the general population). Idiosyncratic ADRs
are less common, often serious, not dose
dependent and show no simple relationship
between the dose and the occurrence of
toxicity or the severity of the reaction. The
toxic reactions may affect many organ systems
either in isolation or combination. The
mechanism of these is not clear but is thought
to include receptor abnormality, abnormality
of a biological system that is unmasked by the
drug, immunological response, drug-drug
interactions, or be multi-factorial.
Adverse drug reaction (ADR) monitoring
involves following steps
1. Identifying adverse drug reaction
(ADR).
2. Assessing causality between drug and
suspected reaction by using various
algorithms.
3. Documentation of ADR in patient’s
medical records.
4. Reporting serious ADRs to
pharmacovigilance centres /ADR
regulating authorities
Identifying the Adverse Drug Reaction
The ADRs produced by a certain new drug are
often recognized when the medication is
undergoing its phase three randomized
controlled trials. Both in the USA and in the
UK there is post marketing surveillance of
ADRs. In the UK this involves reporting
suspected ADRs to the Commission on
Human Medicine using the yellow card
system. In this system new or intensively
monitored medicines should have all
suspected ADRs reported and other medicines
should have any suspected serious ADR
reported. In spite of these mechanisms ADRs
are vastly under reported, 17 and initial reports
of adverse reactions to drugs have taken up to
seven years for trends to begin to appear in the
literature. Under reporting of ADRs is likely to
be due to a number of reasons. Reporting is
not mandatory to clinicians in the UK and so is
likely to be forgotten about amongst the many
other work pressures. A clinician may have
problems recognizing the scenario as an ADR,
because of the background symptoms of the
patient’s original illness. Clinicians might also
be wary of reporting an ADR, because of
worries of inducing a complaint, even in this
no blame culture NHS. It should be pointed
out that the yellow card clearly states you do
not need to be sure if it is or is not an ADR
before you report it. In recognizing an ADR
there are a number of important factors one is
identifying those individuals in whom ADRs
are most likely to occur. This includes the aged
and the premature, those with liver
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IJRPC 2011, 1(3) Srinivasan et al. ISSN: 22312781
Post marketing surveillance
Post marketing surveillance can be done by
different methods:
Anecdotal reporting 18
The majority of the first reports of ADR come
through anecdotal reports from individual
doctors when a patient has suffered some
peculiar effect. Such anecdotal reports need to
be verified by further studies and these
sometimes fail to confirm problem.
Intensive monitoring studies 19,24
These studies provide systematic and detailed
collection of data from well defined groups of
inpatients .The surveillance was done by
specially trained health care professionals who
devote their full time efforts towards
recording all the drugs administered and all
the events, which might conceivably be drug
induced. Subsequently, statistical screening for
drug-event association may lead to special
studies. Popular example for this methodology
is Boston collaborative drug surveillance
program.
Spontaneous reporting system (SRS) 20
It is the principal method used for monitoring
the safety of marketed drugs. In UK, USA,
India and Australia, the ADR monitoring
programs in use are based on spontaneous
reporting systems. In this system, clinicians
encourage reporting any or all reactions that
believe may be associated with drug use
usually, attention is focused on new drugs and
serious ADRs. The rationale for SRS is to
generate signals of potential drug problems, to
identify rare ADRs and theoretically to
monitor continuously all drug used in a
variety of real conditions from the time they
are first marketed. 15
Cohort studies (Prospective studies) 19
In these studies, patients taking a particular
drug are identified and events are then
recorded. The weakness of this method is
relatively small number patients likely to be
studied, and the lack of suitable control group
to assess the background incidence of any
adverse events. Such studies are expensive
and it.
Case control studies (retrospective studies) 18
In these studies, patients who present with
symptoms or an illness that could be due to an
adverse drug reaction are screened to see if
they have taken the drug. The prevalence of
drug taking in this group is then compared
with the prevalence in a reference population
who do not have the symptoms or illness. The
case control study is thus suitable for
determining whether the drug causes a given
adverse event once there is some initial
indication that it might. However, it is not a
method for detecting completely new adverse
reactions.
Case cohort studies 18
The case cohort study is a hybrid of
prospective cohort study and retrospective
case control study, Patients who present with
symptoms or an illness that could be due to an
adverse drug reaction are screened to see if
they have taken the drug. The results are then
compared with the incidence of the symptoms
or illness in a prospective cohort of patients
who are taking the drug.
Record linkage 18
The idea here is to bring together a variety of
patient records like general practice records of
illness events and general records of
prescriptions. In this way it may be possible to
match illness events with drugs prescribed. A
specific example of the use of record linkage is
the so called prescription event monitoring
scheme in which all the prescriptions issued
by selected parishioners for a particular drug
are obtained from the prescription pricing
authority. The prescribers are then asked to
inform those running scheme of any events in
the patients taking the drugs. This scheme is
less expensive and time consuming than other
surveillance methods
Meta analysis 21
Meta analysis is a quantitative analysis of two
or more independent studies for the purpose
of determining an overall effect and of
describing reasons for variation in study
results, is another potential tool for identifying
ADRs and assessing drug safety.
Use of population statistics 22
Birth defect registers and cancer registers can
be used If drug induced event is highly
remarkable or very frequent. If suspicions are
aroused then case control and observational
cohort studies will be initiated.
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IJRPC 2011, 1(3) Srinivasan et al. ISSN: 22312781
II. Causality Assessment Between Drug and
Suspected reaction 23
Causality assessment is the method by which
the extent of relationship between a drug and
a suspected reaction is established.
It is often difficult to decide if an adverse
clinical event is an ADR or due to
deterioration in the primary condition.
Furthermore, if it is an ADR, which medicine
caused it, as many patients are on multiple
new medications when ill, particularly if
admitted to hospital. In spite of these
problems, the decision that a particular drug
caused an ADR is usually based on clinical
judgment alone. Studies have shown that there
is a lot of variation in between rater and
within rater decisions on causality of ADRs;
this applies both to pharmacologists and
physicians 25,26 .
There are various approaches in the first
approach an individual who is an expert in
the area of ADRs would evaluate the case. In
the process of evaluation, he or she may
consider and critically evaluate all the data
obtained to assess whether the drug has
caused the particular reaction. A panel of
experts adopts a similar procedure to arrive at
a collective opinion. using algorithms
including standardization of methods.
Algorithms being structured systems
specifically designed for the identification of
an ADR, should theoretically make a more
objective decision on causality. As such
algorithms should have a better between and
within rater agreement than clinical judgment.
A number of algorithms or decision aids have
been published including the Jones’
algorithm, 28 the Naranjo algorithm, 27 the
Yalealgorithm, 29 the Karch algorithm, 30 the
Begaud algorithm, 31 the ADRAC, 32 the WHO-
UMC, 33 and a newer quantitative approach
Algorithm.34 Each of these algorithms has
similarities and differences. And the most
commonly used algorithms; the Naranjo
algorithm (Fig :1) is shown below
The Naranjo Algorithm is a questionnaire
designed by Naranjo et al for determining the
likelihood of whether an ADR (adverse drug
reaction) is actually due to the drug rather
than the result of other factors. Probability is
assigned via a score termed definite, probable,
possible or doubtful. Values obtained from the
algorithm are sometimes used in peer reviews
to verify the validity of author’s conclusions
regarding adverse drug reactions. It is also
called the Naranjo Scale or Naranjo Score.
III. Documentation of ADRs in Patient’s
Medical Records
This aids as reference for alerting clinicians
and other health care professionals to the
possibility of a particular drug causing
suspected reaction.
IV. Reporting Serious ADRs to
Pharmacovigilance Centres / ADR
Regulating Authorities
According to FDA, a serious reaction is
classified as one which is fatal, life threatening,
prolonging hospitalisation, and causing a
significant persistent disability, resulting in a
congenital anomaly and requiring intervention
to prevent permanent damage or resulting in
death 35 Hatwig SC, Seigel J and Schneider PJ
categorised ADRs into seven levels as per their
severity. Level 1&2 fall under mild category
whereas level 3& 4 under moderate and level
5, 6&7 fall under severe category . 36 (fig:2). Karch
and Lasanga classify severity into minor,
moderate, severe and lethal. In minor severity,
there is no need of antidote, therapy or
prolongation of hospitalisation. To classify as
moderate severity, a change in drug therapy,
specific treatment or an increase in
hospitalization by at least one day is required.
Severe class includes all potentially life
threatening reactions causing permanent
damage or requiring intensive medical care.
Lethal reactions are the one which directly or
indirectly contributes to death of the patient.
Different ADR regulatory authorities are -
Committee on safety of medicine (CSM),
Adverse drug reaction advisory committee
(ADRAC), 37 MEDWATCH, Vaccine Adverse
Event Reporting System 38 WHO-UMC
international database maintains all the data of
ADRs.
CONCLUSION
India has more than half a million qualified
doctors and 15,000 hospitals having bed
strength of 6, 24,000. It is the fourth largest
producer of pharmaceuticals in the world. It is
emerging as important clinical trial hub in the
world. Many new drugs are being introduced
every year and so every health care
professional must have knowledge about
importance of ADR monitoring and
pharmacovigilance. Every health care
professional should see it as a part of his/her
professional duty keeping in mind about
Hippocrates admonition” at least does no
harm”.
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IJRPC 2011, 1(3) Srinivasan et al. ISSN: 22312781
Table 1: Characteristics of Type A and Type B Adverse Reactions
Characteristics Type A Type B
Dose dependency Usually shows good relationship No simple relation ship
Predictable from
known pharmacology
Yes
Not usually
Host factors Genetic factors might be important
Dependent on host
factors
Frequency Common Uncommon
Severity
Variable but usually mild
Variable,
proportionately more
severe
Clinical burden High morbidity and low mortality
High morbidity and
mortality
Overall portion of
adverse drug reaction
80% 20%
First detection
Phase1-III
Phase IV, occasionally
phase III
Animal models Usually reproducible in animals
No known animal
models
Level 1
Level 2
Level 3
Level 4
Level 5
Level 6
Level 7
Table 2: Hartwig’s Severity Assessment Scale
An ADR occurred but required no change in treatment with the suspected drug.
The ADR required that treatment with the suspected drug be held, discontinued, or otherwise
changed. No antidote or other treatment requirement was required. No increase in length of stay
(LOS)
The ADR required that treatment with the suspected drug be held, discontinued, or otherwise
changed.
AND/OR
An Antidote or other treatment was required. No increase in length of stay (LOS)
Mild= level 1 and 2, moderate= level 3 and 4, severe= 5, 6 and 7.
Any level 3 ADR which increases length of stay by at least 1 day . OR
The ADR was the reason for the admission
Any level 4 ADR which requires intensive medical care
The adverse reaction caused permanent harm to the patient
The adverse reaction either directly or indirectly led to the death of the patient
1) Are there previous conclusive reports of this reaction?
If YES = +1, NO = 0, Do not know or not done = 0
2) Did the adverse event appear after the suspected drug was Given?
If YES = +2, NO = -1, Do not know or not done = 0
3) Did the adverse reaction improve when the drug was discontinued or a specific antagonist was given?
If YES = +1, NO = 0, Do not know or not done = 0
4) Did the adverse reaction appear when the drug was Re-administered?
If YES = +2, NO = -2, Do not know or not done = 0
5) Are there alternative causes that could have caused the reaction?
If YES = -1, NO = +2, Do not know or not done = 0
6) Did the reaction reappear when a placebo was given?
If YES = -1, NO = +1, Do not know or not done = 0
7) Was the drug detected in any body fluid in toxic Concentrations?
If YES = +1, NO = 0, Do not know or not done = 0
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IJRPC 2011, 1(3) Srinivasan et al. ISSN: 22312781
8) Was the reaction more severe when the dose was increased or less severe when the dose was decreased?
If YES = +1, NO = 0, Do not know or not done = 0
9) Did the patient have a similar reaction to the same or similar drugs in any previous exposure?
If YES = +1, NO = 0, Do not know or not done = 0
10) Was the adverse event confirmed by any objective evidence?
If YES = +1, NO = 0, Do not know or not done = 0
SCORING
9 = DEFINITE ADR, 5-8 = PROBABLE ADR,
1-4 = POSSIBLE ADR , 0 = DOUBTFUL ADR
Fig. 1: Naranjo Algorithm.
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